Music Exposure in Preterm Infants Leads to Enhanced Cerebral Cortical and White Matter Development 

May 2024

Introduction

This Commentary was stimulated by a recent report in Developmental Cognitive Neuroscience, entitled “Music impacts brain cortical microstructural maturation in very preterm infants: A longitudinal diffusion MR imaging study.”1 The work provides important insight into (a) normal development of the brain in the very preterm infant from 33 to 40 weeks postconceptional age, and (b) the effect of a music intervention during that period on this development. The findings suggest particular value for music exposure in very preterm infants. Although this Commentary focuses on the current report, the study is the most recent of a superb series from the same group focused on the effect of a music intervention in very preterm infants on subsequent structural and functional (connectivity) brain development and behavioral outcomes.2-5

Music Intervention—Study Design

The sample of very preterm infants (mean gestational age 29 weeks) with no overt brain lesions was allocated randomly to a control group (n=19) (no music intervention) or a music intervention group (n=21). MRI (3.0T scanner) was performed during the 33rd week gestational age (GA) and at term equivalent age (TEA). The MRI assessments involved advanced diffusion-based methodologies, i.e., fixel-based analysis (FBA) and neurite orientation dispersion and density imagery (NODDI). FBA provides insight into micro- and macrostructural changes, including such measures as fiber cross-section (FC) and fiber density (FD). NODDI provides microstructural information and, as the name implies, data relevant to neurite density and orientation dispersion.1

The music intervention was carried out two times a day from 33 weeks GA to TEA. The infants were exposed to the music through headphones. (Infants in the no music intervention group were exposed similarly to headphones.) The music was composed of “a calming background, bells, harp, and punji (charming snake flute) interactively creating a melody” of 8 minutes duration. Three different music tracks were available for use, and the track utilized for each exposure was chosen “by the nurse according to the state of wakefulness of the child (waking up, falling asleep, being alert).”1 More detailed assessment of sleep state was not carried out.

The large corpus of data obtained in this report is reviewed best according to insights into brain development during the study period and the effects of the music intervention on this development. To maintain the relative brevity of the Commentary, I will review each of these concisely next.

Brain Developmental Changes 

The advanced MRI measures provided important insight into normal development of multiple structures from the 33rd week GA to TEA. For the sake of convenience, I will divide the structures broadly into cerebral white matter and cerebral cortical gray matter. The imaging features will be correlated with current structural concepts based on direct anatomical studies, the gold standard for assessments of brain development.

Cerebral White Matter

In cerebral white matter, from the 33rd week GA to TEA, prominent increases in FC and FD were observed and are likely indicative of increases in axonal fiber organization, fiber bundle cross-section, axonal coherence and axonal number.1 These indicators of axonal growth and development are consistent with anatomical studies, including studies utilizing GAP-43, a marker of growing axons, and other markers.6-10 Thus, Haynes et al.10 showed abundant expression of GAP-43 in cerebral white matter during this period, as well as expression in cortex, presumably marking the influx of growing axons into overlying cortex at this time. 

The major white matter fibers defined by Sa de Almeida et al. included thalamic, commissural, association, and projection fibers.1 From 33 weeks GA to TEA, the increase in FC and FD observed in thalamic regions is likely a correlate of the well-established growth and elaboration of thalamo-cortical axons7,8,11 occurring particularly in cerebral white matter during this period, as the subplate layer gradually decreases. Also at this time, anatomical studies demonstrate that commissural (callosal), commissural-cortical and corticocortical (association fibers) axons depart the transient subplate and enter cerebral cortex.7,8 Finally, the finding that the most pronounced increases in FD and FC involve central projection fibers (e.g., corona radiata) is consistent with the later myelination order of Kinney (see later) of projection fibers before association fibers.12,13

As will be discussed later, it is possible that the onset of axonal ensheathment by pre-myelinating oligodendrocytes (OLs) accounts for some of the MRI findings. The O4+, O1+ immature OLs that begin this ensheathment are abundant in cerebral white matter as term approaches.14 Indeed, MBP staining of myelin sheaths was demonstrated in periventricular white matter by Back et al.14 as early as 30 weeks GA. However, microscopic myelin, stained by conventional markers (e.g., Luxol Fast Blue), is not detected in cerebral white matter tracts until many weeks or months post-term.12,15 Exceptions to this statement are the central corona radiata and the posterior limb of the internal capsule.

Cerebral Cortical Gray Matter

Important developmental changes were identified by MRI in cortical gray matter.1 FC increased, as it did in white matter, but FD decreased. The findings are most consistent with a decline in the “simple” radial orientation of earlier cortex (created by radially orientated neurons with limited dendritic arbors, and to a lesser extent, by radial glia) and an increase in complexity related to dendritic growth and arborization, influx of axonal ramifications, loss of radial glial fibers with conversion to astrocytes, among other events.7 The findings are reminiscent of the decrease in fractional anisotropy previously shown by DTI.16 The NODDI findings support and expand the conclusion that the changes likely are related to dendritic arborization and disruption of the radial glia scaffold.1 Taken together, the two MRI approaches, FBA and NODDI, provided considerable insight into cortical development from 33-40 weeks GA.

Additionally, Sa de Almeida et al. also consider the cortical gray matter changes as indicative of “intra-cortical myelination” (italics mine).1 This conclusion is the only one in this fine study that I consider problematic. Thus, exhaustive studies of myelination in the human fetus and term infant do not show intracortical myelin at 40 weeks post-conceptional age and overall indicate that myelination within cortex occurs principally over the ensuing months and years post-term.12,17 However, such traditional myelin stains require 7-10 lamellae for detection.13,15,17,18 It could be argued that the MRI data might reflect early ensheathment of axons in cortex by O4+, O1+ immature (pre-myelinating) OLs (which would not stain with traditional myelin stains). Although these cells constitute 50% of the oligodendroglial lineage in periventricular white matter at TEA, they are not present, at least in parietal cortex, at this time.14,19 Thus, sufficient ensheathment by immature Ols to be detected by the myelin stains used by Kinney et al.12,13 and Yakovlev and Lecours17 would not be expected. Moreover, as noted earlier, the sensitive means of detection of myelin, i.e., MBP staining, shows such staining in periventricular white matter and, to a lesser extent, more superficial white matter in human cerebrum at TEA,14 but not in parietal or frontal cortex. Perhaps part of the difficulty in interpreting “myelin” indicators by diffusion-based MRI relates to the very shallow depth of cortex at this time (i.e., only approximately 1.5 mm).20 Is it possible that the MRI findings in the study of Sa de Almeida et al.1 are related to early ensheathment of axons in subcortical association fibers? However, again, I am unaware of clear anatomical evidence for such an occurrence. Thus, at present, the conclusion that “intracortical myelination” was enhanced does not seem plausible to me. This conclusion does not detract from the predominance of new and important findings in this report.

Effects of Early Music Intervention from 33 weeks GA on Brain Maturation Assessed at TEA

The sophisticated MRI assessments at TEA indicate that the music intervention leads to enhanced maturation of both white matter and gray matter structures. Thus, this study and previous work from this group showed enhanced development of several white matter tracts2 consistent with enhanced axonal growth/organization, and, potentially, oligodendroglial differentiation. This finding is consistent with the well-established relation between axonal activity and oligodendroglial differentiation.6,21 These findings likely underlie, at least in part, the enhanced functional connectivity previously shown with the music intervention.3 

The current study indicates that the music intervention also enhanced the maturation of several cortical gray matter regions, especially those involved in auditory, cognitive and socio-emotional processing.1 Coupled with the findings from the NODDI data, the data are consistent with increased dendritic arborization and remodeling of axonal connections leading to enhancement of the overall complexity of the cortical neuropil. Sa de Almeida et al.1 use the term cortical “complexification.” As just noted, the cortical changes are especially apparent in regions (e.g., insulo-orbito-temporopolar complex) which have been related to later socio-emotional deficits commonly observed in follow-up of very preterm infants.1 Notably, earlier work from this group showed that a music intervention during the NICU period was associated with improved “fear-reactivity scores at 12 months and anger-reactivity scores at 24 months,” suggesting a beneficial effect on later socio-emotional development.5 

Also relevant to the enhancement of insular-orbito-temporal connections in these preterm infants are earlier findings in adults that music listening has been shown to activate these cortical regions,22 that auditory cortex is functionally connected to these regions when musical stimuli elicit emotions,1,23 and that music training may lead to re-organization of insular-based networks, potentially enhancing high-level and cognitive and affection functions.1,24 If these beneficial effects could be produced in the developing cerebrum of the preterm infant, the benefits would be appreciable.

Taken together, the role of music intervention in the context of the preterm NICU stay could be substantial over the longer term. Thus, subsequent work assessing the effect of music intervention on a broad range of later neurodevelopmental parameters will be of great interest.

Conclusion

The current work, showing the impact of a music intervention on parameters of cerebral white and gray matter development, sets the stage for future studies assessing a broad range of potential functional effects. The intervention is not complex and should be readily adaptable to current NICUs. As with any intervention in the NICU, however, careful attention to the timing of the activity is important. Disturbance of beneficial sleep states25 would not be desirable. Nonetheless, my view is that the findings are of exceptional interest and could lead to an effective, readily applied neonatal intervention. Future work from this superb group will be of great interest.

Joseph J. Volpe, MD

Department of Neurology, Boston Children’s Hospital

Bronson Crothers Professor of Neurology, Emeritus, Harvard Medical School

Boston MA

References

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